Resveratrol is a polyphenol found in plants and plant-based foods. Resveratrol protects against obesity and obesity-related diseases such as type 2 diabetes. The mechanism by which resveratrol confers these benefits is not known. We discovered that the metabolic benefits of resveratrol are mediated by inhibiting phosphodiesterase 4 in skeletal muscle. Resveratrol has also been reported to activate Sirt1. In mammals, the Sirtuins are composed of seven Sir2 orthologues (Sirt1-7) with a conserved deacetylase core that utilizes NAD+ as a cofactor. Sirtuins play an important role in energy metabolism and regulating Sirtuin activity may be useful for controlling fat accumulation. We found that resveratrol increases Sirt1 activity by increasing NAD+ in an AMPK-dependent manner.